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Crohn's disease (CD) is an idiopathic chronic inflammatory bowel disease (IBD). IBD can be divided into two different forms which are ulceration colitis and Crohn's disease. Ulceration colitis is a mucosal inflammatory disorder that located rectum and colon. However, CD is a transmural granulomatous inflammation of GI mucosa [i] and may affect any part of the GI tract. It mostly occurs at terminal ileum and proximal colon. Sometimes, it may associate with inflammatory disorder of spine, skin and eyes. [ii]
A recent study shows that there is an increase of prevalence and incidence rates of CD in US and Europe. The prevalence is about 144.8 cases per 100 000 and the incidence rate is around 5-10 per 100 000/year in UK. [iii] , [iv] Mortality is showed to be highest in the first 4 to 5 years after diagnosis. 93.7% of the general population have 15 years of survival. 25% of the patients are unable to work in first year after diagnosis and 15% of the patients are unable to work after 5-10 years. The longer the duration of illness, the higher the chance of death and complication developed in patient. Patients with ileal or ileocecal have a lower risk of mortality comparedÂ with those who have proximal small bowel disease. [v]
CD thickens the intestinal mucosa and proliferation of the endothelium within the bowel. As the disease progresses, the segment of bowel becomes thick and rigid just looks like a 'horse-pipe' appearance. Unlike ulceration colitis, CD patient always have unaffected bowel segments between disease sites. [vi] This can be referred as 'skip lesions'. The actual cause of CD is unknown. However, research shows that GI inflammation of patient with CD mostly involves gene inherited by patient, immune system itself, infection and environment. Dysregulated immune responses might be primary cause of CD. Long term of abnormal activation of immune system in the absence of any invader will result in chronic inflammation and ulceration. Mutations of NOD2/CARD15 gene expression in macrophages and intestinal epithelial cells can increase the risk of CD as well. Diet such as low fibre and high carbohydrate is believed to contribute to the development of CD. Environmental factors such as smoking seem to affect the CD and smokers are 3-4 times higher risk to develop CD compared to non-smokers. NSAIDs may exacerbate disease as well.3
Symptoms are varied due to inflammation of the different parts in the gut. Patient with severe exacerbate CD will be in very poor general health, with weight loss, perhaps fever, severe abdominal pain and frequent diarrhoea. [vii] Frequent diarrhoea may lead to electrolytes imbalance. Weight loss may be due to malabsoroption that caused by anorexia. Deficiency of Vitamin B12, folate, iron and blood loss may cause anaemia in CD patient as well. Patient my experience abdominal pain, blood, pus and mucus in the stool if disease occurs in colon. [viii] Others long-term medical consequences include ileocolic disease, vitamin B12 malabsoprion, chronic bleeding, protein-losing enteropathy, and extraintertinal disease. [ix] Severe active CD would usually have a score of CDAI (Crohn's Disease Activity Index) > 300 or at least 8 to 9 on the Harvey-Bradshaw Index. [x]
Intestinal tract and other organs always involved in complications of Crohn's disease. Common complications include perianal diseases such as aphthous ulceration, haemorrhoid, perirectal abcesses and fistulae. [xi] Sometimes, strictures and perforation may be developed. Fistulae normally occur in small intestinal and the symptoms are depending on the site of disease. Scarring of inflammation in the intestine may develop strictures. However, perforations are rarely happen in CD. In addition, CD also will increase risk of toxic dilatation and colonic carcinoma in patients. [xii] Some extraintestinal signs such as clubbing, erythema nodosum, pyoderma gangrenosum, conjunctivitis, fatty liver and sacroiliitis may occur as well. [xiii]
The presentation of CD is highly variable. It makes the prognosis of the patient becomes exceedingly difficult. The CD is characterised by periods of remission and exacerbation. Some patients may be free from any symptoms for years whereas others may experience chronic symptoms despite they are under medical therapy. There is a relentless progression of the disease and a high incidence of complications when patients are followed over a long period.
With those clinical presentations mentioned above, Crohn's disease can be diagnosed by radiography and it is better to be confirmed with endoscopy and biopsy.9 Differential diagnoses include ulcerative colitis, acute appendicitis, small bowel obstruction, malabsorption syndrome, irritable bowel syndrome, neoplasia, diverticular disease, haemorrhoid and antibiotic-associated colitis.
Oral mesalazine 3-4g/day or metronidazole. Budesonide 9mg/day for terminal ileal or ascending colonic disease
Ileocolonic or colonic
Oral mesalazine 3-4g/day
Sulfasalazine/oral mesalazine/metronidazole up to 10-20mg/kg/day
Taper prednisolone after 2-3 wk Response
Refractory and fistulizing disease - add infliximab
As above plus prednisolone 40-60mg
Add azathioprine, mercaptopurine, or methotrexate or switch to adalimumab
Cyclosporine IV 4mg/kg/day
Hydrocortisone 100mg IV every 6-8h
No response in 7 days
Figure 1: Treatment approaches for Crohn's disease1
CD can be classified into three categories which are mild to moderate, moderate to severe and severe disease. The severity is difficult to assess in CD. The aim of treatment in this case is to clear symptoms and to achieve remission. Site (colonic, ileal and others), pattern (fistulating, inflammatory, stricturing), and activity are the general points that have to be considered before start the treatment. [xiv] There are no established NICE or SIGN guidelines for the treatment of Crohn's disease.
Treatments of CD include modification of lifestyle, pharmacological treatment, nutrition therapy and surgery. Pharmacological treatments involve induce remission of active disease and maintenance of remission.1 In majority of patients, active CD is treated with sulfasalazine, mesalazine derivatives, or steroids. Azathiopurine, mercaptopurine, methotrexate, infliximab, and metronidazole are frequently used as well.i
Treatment for severe exarcebation crohn's disease
Corticosteroids have been widely used as potent anti-inflammatory agents for treatment of CD and usually used in moderate to severe disease.xv Corticosteroids are particularly used in more severe presentations or in patients who have no response to aminosalicylate. Prednisolone is most commonly used. Budesonide is an oral controlled- release formulation that minimizes systemic effect.i
They act via a receptor-mediated mechanism and combine with the receptor in cytoplasm, which then enter the nucleus and binds to a steroid response element. This alters mRNA production and protein synthesis. This will stimulate the formation of endogenous phospholipase A2 inhibitor, lipocortin. Hence, the release of arachidonate from cell membrane is prevented. Thus, deprives both cyclo-oxygenase and lipoxygenase of substrate. The formation of both leukotrines and prostanoids are prevented as well. Corticosteroids also reduce leukocyte infiltration at the site of inflammation, suppress the humoral immune response and interfere in the function of inflammatory mediators. They also help to slow down the inflammatory process, reduce scar tissue or oedema and suppress production of antibody.
Normally, severe exacerbation of CD will be treated with hydrocortisone 100mg IV every 6-8 hours to suppress inflammation and provide rapid symptomatic relief. Studies showed that systemic steroid induce remission up to 70%. Topical steroids for example hydrocortisone 100mg in 100ml 0.9% saline/12 hr per rectum is also given to treat rectal disease.vi If symptoms improved after 5 days, hydrocortisone IV can be replaced by oral prednisolone for example 40mg/day. However, if patient is not response to hydrocortisone IV, cyclosporine IV 4mg/kg/day should be given or seek surgical advice.i
Two major trials have found that corticosteroids are very effective for inducing remission in crohn's disease. The National Co-operative CD showed that 162 randomised patient with predisolone 0.5-0.75mg/kg/day have achieved 60% remission and tapering over 17 weeks if compared to placebo group which is only 30% remission (NNT=3). [xv] Another study European Cooperative Crohn's Disease Study (ECCDS): Colonoscopy showed that for 105 patients, 83% remission has been achieved for prednisolone 1mg/kg/day compared to 38% of placebo group (NNT=2). [xvi] Prednisolone is preferably taken in the morning after the breakfast. Then continued until remission occur, followed by reducing dose.
However, steroids have no place in maintenance treatment of CD due their nasty side effects include GI disturbance, fluid retention, muscle weakness, headache, high blood pressure, potassium loss, hirudism and puffiness, psychic disturbance and so on. Long-term use of steroids can cause adrenal suppression. Hence, the treatment must not be stopped abruptly because ability of body's adrenal gland to produce corticosteroid has been suppressed. The dose has to be gradually withdrawn to prevent corticosteroid deficiency. Cortisosteroid will also cause immunosupression which will impair body's immune response and increase susceptibility to infections. Osteoporosis is also one of the common site effects of steroids. Calcium and vitamin D supplement should be given to the patient who is having long-term usage of steroids.xv
Metronidazole is used for treating infections that develope because of CD. The drug enters into microorganism and promotes formation of intermediate compounds and free radicals that are toxic to the cell. 400mg/8h PO or 500mg/8h IV of metronidazole are frequently used in attempts to control CD especially in fistula and perianal disease.
A double blind study has been carried out to compare efficacy between metronidazole and placebo in patient with CD. As a result, metronidazole was found to be more effective than placebo especially in patients with disease that involve in large intestine or large bowel area. [xvii] The drug is normally given no longer than 3 months because it may cause development of peripheral neuropathy. Consuming alcohol and metronidazole at the same time will lead to disulfiram-like reaction. Other side effects include GI disturbance, taste disturbance and anorexia.
Infliximab is an anti-tumour necrosis factor monoclonal antibody which is highly effective in controlling the symptoms of disease. It counters neutrophil accumulation and granuloma formation. Then activates complement and causes cytotoxicity to CD4+ T-cells. Thus, clearing cell driving the immune response.vi
A double blind study for 108 patients with severe active CD refractory to corticosteroids, immunosuppressive agents and 5-ASA has shown 81% response rate from patients who were taking 5mg/kg infliximab infusion compared to 17% from placebo group. [xviii] There were few more clinical trials also proved that inflicimab is a effective drug for patients with moderate to severe active CD and fail in immunosuppressive therapy, treatment for fistulising disease, in those who are corticoid dependent and when surgery is inappropriate. Although some studies had comfirmed that infliximab is effective in maintaining remission of CD, it is not yet licensed in NICE guideline for maintenance of remission. [xix]
Infliximab cost far exceeds that of other regimens. Side effects of infliximab include nausea, abdominal pain, worsening heart failure, hypersensitivity reactions, fever, headache, depression and so on.
Cyclosporine is an immunosuppressive agent that binds to cyclophilin of T-lymphocyte and form a complex of cyclosporine and cyclophilin. This complex will inhibit calcineurin, which is responsible to activate transcription of interleukin 2 under normal conditions. By binding to cyclophilin, dephosphorylation of nuclear factor of activated T-cells (NF-AT) also can be prevented. Cylosporine also inhibits interleukin release and lymphokine production.
Cyclosporine is not recommended for CD except for patients with symptomatic, severe perianal or cutaneous fistula and no response to IV hydrocortisone. The dose of cyclosporine is a very important factor to determine the efficacy of the drug. A meta-analysis that included four randomised trial has been carried out to prove that low dose of cyclosporine (<5mg/kg/day) was not effective. Whereas, >5mg/kg/day was effective. However, high dose of cyclosporine is not recommended for chronic treatment due to toxic effect such as nephrotoxicity. [xx] Dose should be guided by cyclosporine whole-blood concentration. Side effects of cyclosporine include GI disturbance, hepatic dysfunction, anorexia, hypertension, tremor, headache and fatigue.xv
IV hydration/ IV nutrition
Malnutrition and dehydration are very common in CD. Vomiting, diarrheao and fever can cause patient to become dehydrated fairly quickly. Patients with moderate to severe CD are often malnourished. Hence in severe case, intravenous fluid and electrolyte replacement, and possibly parental nutrition can be administered to the patient. For example IV hydration such as 1L 0.9% saline + 2L dextrose-saline/24h + 20mmol K+/L can be given to the patient. Additional electrolytes like potassium, magnesium, bicarbonate, chloride and calcium, vitamins, or drugs can be added to the IV solution by injecting them into the bottle or bag with a needle.
50% of patients will require surgical treatment for first 10 years after the diagnosis and 70-80% of CD patient will require for surgical treatment in their lifetime.xiv However, surgery should only be considered if there is no response during IV therapy, deterioration of disease and complications such as intestinal obstruction from strictures, intestinal perforation and local complications (fistulae, abscesses). Surgery is never curative. The aims are to alleviate complications, conserve functional bowel region and improve quality of life of patients. Types of surgery include resection, colectomy, proctocolectomy and surgery for Abscesses and Fistulas. Recurrence rate of CD will be increased after surgery.
Other treatments for active crohn's disease
Aminosalicylates (sulfasalazine, mesalazine, olsalazine and balsalazine) are the basis of drug treatment for inflammatory bowel disease. The exact mechanism of aminosalicylate is still unknown.xiv Sulfasalazine is more effective when CD involves colon. Mesalazine derivatives such as Pentasa and Asacol may be more effective for ileal involvement.xv
Sulfasalazine and mesalazine are very effective in treatment of active CD. However, they have shown to be less effective for maintaining remission in CD. [xxi] Based on the meta-analysis of studies published up to October 1993, 5-ASA did show the reduction of risk of relapse for CD. However, these reductions were not statistically significant. [xxii] Aminosalicylates should be avoided in salicylate hypersensitivity and should be used with caution in renal impairment, during pregnancy and breast-feeding. Blood disorder may occur when the patient is taking aminosalicylate. Other side effects include diarrhoea, nausea, vomiting, abdominal pain and headache.xiv
Thiopurines such as azathioprine and mercaptopurine are effective for both active disease and therapy for maintenance of remission.vi However, they are generally used in patients who are less response to standard medical therapy or for the cases that are refractory to steroids which may cause serious adverse effects such as lymphomas, pancreatitis or nephrotoxicity.i Azathioprine is a DNA synthesis inhibitor. It will transform to a purine analogue and inhibit proliferation of cells. 6-mercaptopurine interfere the synthesis of RNA and DNA ribonucleotide by inhibiting purine nucleotide synthesis and metabolism. Mercaptopurine also alters glycoprotein synthesis and nucleotide interconversion.
Two Cochrane reviews have confirmed that azathioprine and mercaptopurine are effective therapy for inducing remission in active CD and they are also more effective than placebo for maintenance of remission in CD. [xxiii] , [xxiv] Patients with thiopurine S-methyltransferase (TPMT) deficiency will have higher chance to get bone marrow suppression which caused by azathioprine and mercaptopurine. Hence, determination of TPMP genotype is recommended before start the treatment. Other side effects include hypersensitivity reaction, hair loss, liver impairment and increase susceptibility to infections in patients who are also receiving corticosteroids.xv
Methotrexate is a folate antagonist that blocks synthesis of DNA. Thus inhibits lymphocyte production. It also inhibits cytokine and ecosanoid synthesis. Normally methotrexate is given by 25mg IV weekly for induction of remission in CD as well as for maintenance therapy.
A Cochrane review found that more patients in methotrexate group can withdraw steroids and enter into remission compared to placebo group. [xxv] 25mg IM weekly is effective for induction remission and also maintenance of remission compared to placebo (65% vs. 39%). [xxvi] Patients are warned to report immediately if there is any features of blood disorder, liver toxicity and respiratory effects. Folic acid is recommended to prevent folic acid deficiency that caused by methotrexate.
For severe exacerbation attack of crohn's disease, patient should be admitted for IV steroids such as hydrocortisone and IV hydration. Metronidazole is frequently used when perianal or fistulas are involved. Temperature, pulse, blood pressure have to be monitored and stool frequency and character is recorded on a stool chart. Physical examination has to carry out twice daily. FBC, ESR, U&E and plain AXR need to be measured daily. Blood transfusion (if Hb<10g/dL) and parental nutrition can be considered as well. If patient's condition improves after 5 days, IV steroids can be transfer to oral prednisolone. If no response during IV therapy, surgery can be considered.